Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Short Communication
  • Published:

Estradiol downregulates NF-κb translocation by Ikbkg transcriptional repression in dendritic cells

Genes & Immunity volume 14, pages 462–469 (2013)Cite this article

Subjects

Abstract

To reconcile immunity and reproduction, females must allow spermatozoa to survive and control the presence of commensal microbiota and sexually transmitted pathogens during ovulation. Female steroid sex hormones exert a powerful effect on the immune system, as do the hormonal changes associated with the ovarian cycle. Dendritic cells (DCs) are immunological sentinels that link innate immunity to adaptive immunity. Upon exposure to microbial invaders in tissue, they undergo a maturational process that culminates in the lymph nodes and activates T-cell-specific immune responses. Estradiol, which is highly expressed during ovulation, has an effect on the maturation of DCs, although the molecular mechanism remains elusive. We detected that estradiol regulates expression of Ikbkg in DCs and modulates nuclear factor-κb translocation to the nucleus, thus explaining the reduced DC function observed during ovulation. This change may be an adaptive mechanism to reconcile control of infection and reproductive functions.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Brabin L, Brabin BJ . Parasitic infections in women and their consequences. Adv Parasitol 1992; 31: 1–81.

    Article  CAS  Google Scholar 

  2. Daniels CW, Belosevic M . Serum antibody responses by male and female C57Bl/6 mice infected with Giardia muris. Clin Exp Immunol 1994; 97: 424–429.

    Article  CAS  Google Scholar 

  3. Komukai Y, Amao H, Goto N, Kusajima Y, Sawada T, Saito M et al. Sex differences in susceptibility of ICR mice to oral infection with Corynebacterium kutscheri. Exp Anim 1999; 48: 37–42.

    Article  CAS  Google Scholar 

  4. Giron-Gonzalez JA, Moral FJ, Elvira J, Garcia-Gil D, Guerrero F, Gavilan I et al. Consistent production of a higher TH1:TH2 cytokine ratio by stimulated T cells in men compared with women. Eur J Endocrinol 2000; 143: 31–36.

    Article  CAS  Google Scholar 

  5. Beagley KW, Gockel CM . Regulation of innate and adaptive immunity by the female sex hormones oestradiol and progesterone. FEMS Immunol Med Microbiol 2003; 38: 13–22.

    Article  CAS  Google Scholar 

  6. Whitacre CC, Reingold SC, O'Looney PA . A gender gap in autoimmunity. Science 1999; 283: 1277–1278.

    Article  CAS  Google Scholar 

  7. Hughes GC, Clark EA . Regulation of dendritic cells by female sex steroids: relevance to immunity and autoimmunity. Autoimmunity 2007; 40: 470–481.

    Article  CAS  Google Scholar 

  8. Ober C, Loisel DA, Gilad Y . Sex-specific genetic architecture of human disease. Nat Rev Genet 2008; 9: 911–922.

    Article  CAS  Google Scholar 

  9. Wira CR, Fahey JV . A new strategy to understand how HIV infects women: identification of a window of vulnerability during the menstrual cycle. AIDS 2008; 22: 1909–1917.

    Article  Google Scholar 

  10. Nilsson S, Gustafsson JA . Biological role of estrogen and estrogen receptors. Crit Rev Biochem Mol Biol 2002; 37: 1–28.

    Article  CAS  Google Scholar 

  11. Dunbar B, Patel M, Fahey J, Wira C . Endocrine control of mucosal immunity in the female reproductive tract: impact of environmental disruptors. Mol Cell Endocrinol 2012; 354: 85–93.

    Article  CAS  Google Scholar 

  12. De Bernardis F, Lucciarini R, Boccanera M, Amantini C, Arancia S, Morrone S et al. Phenotypic and functional characterization of vaginal dendritic cells in a rat model of Candida albicans vaginitis. Infect Immun 2006; 74: 4282–4294.

    Article  CAS  Google Scholar 

  13. LeBlanc DM, Barousse MM, Fidel PL Jr . Role for dendritic cells in immunoregulation during experimental vaginal candidiasis. Infect Immun 2006; 74: 3213–3221.

    Article  CAS  Google Scholar 

  14. Romani L, Montagnoli C, Bozza S, Perruccio K, Spreca A, Allavena P et al. The exploitation of distinct recognition receptors in dendritic cells determines the full range of host immune relationships with Candida albicans. Int Immunol 2004; 16: 149–161.

    Article  CAS  Google Scholar 

  15. Cambi A, Netea MG, Mora-Montes HM, Gow NA, Hato SV, Lowman DW et al. Dendritic cell interaction with Candida albicans critically depends on N-linked mannan. J Biol Chem 2008; 283: 20590–20599.

    Article  CAS  Google Scholar 

  16. Buelens C, Verhasselt V, De Groote D, Thielemans K, Goldman M, Willems F . Human dendritic cell responses to lipopolysaccharide and CD40 ligation are differentially regulated by interleukin-10. Eur J Immunol 1997; 27: 1848–1852.

    Article  CAS  Google Scholar 

  17. Sallusto F, Schaerli P, Loetscher P, Schaniel C, Lenig D, Mackay CR et al. Rapid and coordinated switch in chemokine receptor expression during dendritic cell maturation. Eur J Immunol 1998; 28: 2760–2769.

    Article  CAS  Google Scholar 

  18. Israel A . The IKK complex, a central regulator of NF-kappaB activation. Cold Spring Harb Perspect Biol 2010; 2: a000158.

    Article  Google Scholar 

  19. Reis e Sousa C . Dendritic cells in a mature age. Nat Rev Immunol 2006; 6: 476–483.

    Article  CAS  Google Scholar 

  20. Rescigno M, Citterio S, Thery C, Rittig M, Medaglini D, Pozzi G et al. Bacteria-induced neo-biosynthesis, stabilization, and surface expression of functional class I molecules in mouse dendritic cells. Proc Natl Acad Sci USA. 1998; 95: 5229–5234.

    Article  CAS  Google Scholar 

  21. Yang L, Hu Y, Hou Y . Effects of 17beta-estradiol on the maturation, nuclear factor kappa B p65 and functions of murine spleen CD11c-positive dendritic cells. Mol Immunol 2006; 43: 357–366.

    Article  CAS  Google Scholar 

  22. Kyurkchiev D, Ivanova-Todorova E, Hayrabedyan S, Altankova I, Kyurkchiev S . Female sex steroid hormones modify some regulatory properties of monocyte-derived dendritic cells. Am J Reprod Immunol 2007; 58: 425–433.

    Article  CAS  Google Scholar 

  23. Uemura Y, Liu TY, Narita Y, Suzuki M, Matsushita S . 17 Beta-estradiol (E2) plus tumor necrosis factor-alpha induces a distorted maturation of human monocyte-derived dendritic cells and promotes their capacity to initiate T-helper 2 responses. Hum Immunol 2008; 69: 149–157.

    Article  CAS  Google Scholar 

  24. Segerer SE, Muller N, van den Brandt J, Kapp M, Dietl J, Reichardt HM et al. Impact of female sex hormones on the maturation and function of human dendritic cells. Am J Reprod Immunol 2009; 62: 165–173.

    Article  CAS  Google Scholar 

  25. Escribese MM, Kraus T, Rhee E, Fernandez-Sesma A, Lopez CB, Moran TM . Estrogen inhibits dendritic cell maturation to RNA viruses. Blood 2008; 112: 4574–4584.

    Article  CAS  Google Scholar 

  26. Relloso M, Aragoneses-Fenoll L, Lasarte S, Bourgeois C, Romera G, Kuchler K et al. Estradiol impairs the Th17 immune response against Candida albicans. J Leukoc Biol 2012; 91: 159–165.

    Article  CAS  Google Scholar 

  27. Bourdeau V, Deschenes J, Metivier R, Nagai Y, Nguyen D, Bretschneider N et al. Genome-wide identification of high-affinity estrogen response elements in human and mouse. Mol Endocrinol 2004; 18: 1411–1427.

    Article  CAS  Google Scholar 

  28. Hua S, Kallen CB, Dhar R, Baquero MT, Mason CE, Russell BA et al. Genomic analysis of estrogen cascade reveals histone variant H2A.Z associated with breast cancer progression. Mol Syst Biol 2008; 4: 188.

    Article  Google Scholar 

  29. Fullwood MJ, Liu MH, Pan YF, Liu J, Xu H, Mohamed YB et al. An oestrogen-receptor-alpha-bound human chromatin interactome. Nature 2009; 462: 58–64.

    Article  CAS  Google Scholar 

  30. Welboren WJ, van Driel MA, Janssen-Megens EM, van Heeringen SJ, Sweep FC, Span PN et al. ChIP-Seq of ERalpha and RNA polymerase II defines genes differentially responding to ligands. EMBO J 2009; 28: 1418–1428.

    Article  CAS  Google Scholar 

  31. Zhao T, Yang L, Sun Q, Arguello M, Ballard DW, Hiscott J et al. The NEMO adaptor bridges the nuclear factor-kappaB and interferon regulatory factor signaling pathways. Nat Immunol 2007; 8: 592–600.

    Article  CAS  Google Scholar 

  32. Temmerman ST, Ma CA, Borges L, Kubin M, Liu S, Derry JM et al. Impaired dendritic-cell function in ectodermal dysplasia with immune deficiency is linked to defective NEMO ubiquitination. Blood 2006; 108: 2324–2331.

    Article  CAS  Google Scholar 

  33. Karamchandani-Patel G, Hanson EP, Saltzman R, Kimball CE, Sorensen RU, Orange JS . Congenital alterations of NEMO glutamic acid 223 result in hypohidrotic ectodermal dysplasia and immunodeficiency with normal serum IgG levels. Ann Allergy Asthma Immunol 2011; 107: 50–56.

    Article  CAS  Google Scholar 

  34. Bedford JM, Mock OB, Phillips DM . Unusual ampullary sperm crypts, and behavior and role of the cumulus oophorus, in the oviduct of the least shrew. Cryptotis parva. Biol Reprod 1997; 56: 1255–1267.

    Article  CAS  Google Scholar 

  35. Suarez SS . Regulation of sperm storage and movement in the mammalian oviduct. Int J Dev Biol 2008; 52: 455–462.

    Article  Google Scholar 

  36. Yang L, Li X, Zhao J, Hou Y . Progesterone is involved in the maturation of murine spleen CD11c-positive dendritic cells. Steroids 2006; 71: 922–929.

    Article  CAS  Google Scholar 

  37. Liang J, Sun L, Wang Q, Hou Y . Progesterone regulates mouse dendritic cells differentiation and maturation. Int Immunopharmacol 2006; 6: 830–838.

    Article  CAS  Google Scholar 

  38. Paharkova-Vatchkova V, Maldonado R, Kovats S . Estrogen preferentially promotes the differentiation of CD11c+ CD11b(intermediate) dendritic cells from bone marrow precursors. J Immunol 2004; 172: 1426–1436.

    Article  CAS  Google Scholar 

  39. Mao A, Paharkova-Vatchkova V, Hardy J, Miller MM, Kovats S . Estrogen selectively promotes the differentiation of dendritic cells with characteristics of Langerhans cells. J Immunol 2005; 175: 5146–5151.

    Article  CAS  Google Scholar 

  40. Israel A, Kimura A, Kieran M, Yano O, Kanellopoulos J, Le Bail O et al. A common positive trans-acting factor binds to enhancer sequences in the promoters of mouse H-2 and beta 2-microglobulin genes. Proc Natl Acad Sci USA. 1987; 84: 2653–2657.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to the units of confocal microscopy, flow cytometry and statistical analysis, as well as to the animal facility of the Instituto de Investigación Sanitaria Gregorio Marañón, for their help and support. R. Madrid, V. Briz, M. Martínez-Bonet, and R. Gonzalez-Dosal provided corrections and comments. F. Sanchez-Cobos provided technical support. This work was supported by research grants from Instituto de Salud Carlos III (ISCIII) (PI10/00897) and Fundacion Mutua Madrileña (awarded to MR). MR holds a Miguel Servet contract from the ISCIII (CP08/00228). MAMF hold grants from the ISCIII (INTRASALUD PI09/02029). LALF holds a Miguel Servet contract from ISCIII (CP06/00267).

Author information

Authors and Affiliations

  1. Laboratorio InmunoBiología Molecular, Hospital General Universitario Gregorio Marañón and Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain

    S Lasarte, D Elsner, A Fernandez-Pineda, M A Muñoz-Fernandez & M Relloso

  2. Faculty of Medicine, Southampton General Hospital, Southampton, UK

    T Sanchez-Elsner

  3. Laboratory of Pharmacogenetics and Pharmacogenomics, Hospital General Universitario Gregorio Marañón and Instituto de Investigación Sanitaria del Hospital Gregorio Marañón, Madrid, Spain

    L A López-Fernández

  4. Centro de Investigaciones Biológicas, Madrid, Spain

    A L Corbí

Authors
  1. S Lasarte
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D Elsner
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. T Sanchez-Elsner
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A Fernandez-Pineda
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. L A López-Fernández
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A L Corbí
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M A Muñoz-Fernandez
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M Relloso
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M Relloso.

Ethics declarations

Competing interests

The authors declare no conflicts of interest.

Additional information

Supplementary Information accompanies this paper on Genes and Immunity website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lasarte, S., Elsner, D., Sanchez-Elsner, T. et al. Estradiol downregulates NF-κb translocation by Ikbkg transcriptional repression in dendritic cells. Genes Immun 14, 462–469 (2013). https://doi.org/10.1038/gene.2013.35

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/gene.2013.35

Keywords

Search

Advanced search

Quick links